Project Summary/Abstract The thalamic reticular nucleus (TRN), is a shell like structure that surrounds the dorsal thalamus and serves as a key inhibitory interface for the bidirectional signaling between thalamus and the neocortex. Together with inputs from thalamus, cortex, and cholinergic nuclei of brainstem and basal forebrain, the TRN regulates many aspects of sensory, motor, and cognitive processing. When the connections between these structures are disrupted by disease, degeneration, or trauma, they have devastating consequences. In fact, many adult and childhood neurological disorders have at their core, a disturbance in TRN signaling and circuitry. Despite its key role in thalamocortical function, remarkably little is known about how reticular circuitry emerges during development and becomes operational. To address this substantive gap in knowledge we developed a robust mouse model as an experimental platform to visualize, manipulate, and dissect emergent and developing reticular circuitry. We plan to conduct anatomical, electrophysiological, and optogenetic experiments in genetically modified mice that allow for the visualization and experimental manipulation of specific cell types arising from the TRN, first-order thalamic sensory nuclei, layer VI of cortex, and cholinergic nuclei of brainstem and basal forebrain. The goals of this proposal focus on three unanswered questions about TRN development. First, how are the sensory sectors of TRN established; do inputs from primary sensory thalamic nuclei and corresponding regions of cortex innervate TRN diffusely and then segregate to form modality specific domains? Second, what is the sequence and pattern of driver and modulator innervation of TRN; do driver-like inputs from sensory thalamic nuclei such as the dorsal lateral geniculate nucleus, arrive prior to modulatory input from cortex, or brainstem and basal forebrain? Third, how and when do feed-forward and feedback circuits linking TRN to thalamus and cortex emerge during development to control thalamocortical signaling? Finally, for each of these questions, we plan to take a loss of function approach to assess whether the absence of sensory input (vision) affects the development, form, and function of reticular circuitry. These studies will provide valuable information about the organizing principles that guide the emergence of reticular circuitry in the neonatal brain, and perhaps reveal a new understanding into childhood disorders that result from abnormal patterns of connectivity.